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ISSN: 2157-7439
Journal of
Nanomedicine & Nanotechnology
Muneer et al., J Nanomed Nanotechnol 2017, 8:3
DOI: 10.4172/2157-7439.1000448
Review Article
OMICS International
Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review
Muneer S1,2,3*, Masood Z1, Butt S1, Anjum S1, Zainab H1, Anwar N1 and Ahmad N1
Faculty of Pharmacy, University of Lahore, Pakistan
Faculty of Pharmacy, University of Karachi, Pakistan
3
Pharmacy Australia Center of Excellence, University of Queensland, Australia
1
2
Abstract
Liposomes, the microscopic vesicles, are composed of a bilayer of phospholipids and a novel drug delivery
system that provides drug at predetermined rate decided according to need, pharmacological aspects, drug profile,
physiological conditions of body etc. But liposomes exhibit poor stability problem and this leads to their storage problem.
To circumvent this problem Pro-liposomes (PLs) were discovered in 1986. Pro-liposomes are free flowing granular
products composed of drug and phospholipid precursors which on hydration lead to liposomes. This paper reviews
various features regarding pro-liposomes, their method of preparation, evaluation, applications and pointing out its
potential to be employed for different routes of administration.
Keywords: Liposome; Pro-liposome; Carriers; Phospholipids;
Cholesterol
• Fluidized-bed method.
• Supercritical anti-solvent method.
Introduction
Film deposition on carrier method
The liposomes were first described by British haematologist Dr.
Alec D Bangham in 1961 at the Babraham Institute, in Cambridge.
Liposome is derived from Greek words: “Lipos” meaning fat and “Soma”
meaning body [1]. Out of all the novel drug delivery systems, liposomes
are considered to be the most effective, researched and broadly [2].
A micro spherical vesicle consisting of an aqueous core enclosed in
phospholipid molecules is known as liposome. Drug molecules can
be incorporated into the aqueous phase or within the lipid bilayer.
They are widely used as a vehicle for administration of nutrients and
pharmaceutical drugs to improve the stability and effectiveness of
drug by reducing the side effects [3]. To enter the market, Liposomes
should remain stable and intact during the storage period and before
reaching the targeted site to produce therapeutic action. However, due
to physical and chemical instability, liposomes are relatively unstable
colloidal systems [4].
Film deposition on carrier method is used for the composition of
Pro-liposomes. In this procedure, the coat of drug and phospholipids
is discharged on a pervious, water soluble carrier substance. By
viewing Figure 1, an evaporative solution containing a solution of
drug and phospholipids is injected drop by drop by a feed tube onto
a core of carrier substance which is carried in a vessel of a rotary flash
evaporator under vacuum. At any stated moment, the matrix’s overwetting is circumvented and following aliquot of organic mixture is
feeding solely when a free flowing powder matrix is procured [10].
Selected carriers should exhibit great surface area and permeability in
order to regulate the quantity of carrier which is needed to assist the
lipids. This also permits great surfactant to carrier mass proportion for
the pro-liposomes production. As they are water soluble, they enable
fast production of liposomal dispersion on hydration and by properly
managing the size of pervious powder, comparatively limited variety
of reconstituted liposomes can be acquired. Mostly used carriers
are maltodextrin, sorbitol, microcrystalline cellulose, magnesium
aluminum silicates, mannitol, etc. [11]. Stride of solvent inclusion
and evaporation which is sluggish [12]. To circumvent this issue, alter
the procedure by dispersing the carrier substance in organic mixture
of drug and phospholipids in vessel of rotary evaporator and then
directing it to vacuum evaporation. By doing so, highly consistent and
well-organized lipid distribution is achieved and a steady and less time
taking procedure is gained in contrast to the actual procedure [13].
Liposomal suspension may have limited shelf life and to overcome
the stability issue associated with liposome, a new “pro-liposome”
method is developed that can produce liposomes quickly when there
is a need and without excessive manipulation [5]. Pro-liposomes
(PLs) were discovered in 1986 [6]. Pro-liposomes are dry, free-flowing
granular products that on hydration or on contact with biological
fluids in the body, form liposomal dispersion. They are composed of
water soluble porous powder and phospholipid [7].
For producing commercial liposome products, Pro-liposome is
one of the most widely used and cost-effective methods. As they are
available in dry powder form, it’s easy to distribute, transfer, measure
and store, making it a diverse system. Liposomes can either be formed
in vivo by the influence of biological fluids in the body or in vitro using
a suitable hydrating fluid before the administration [8]. Solubility and
bioavailability problems of many drugs can be overcome by developing
pro-liposomal formulations [9].
Method of Preparation
Pro-liposomes (PLs) are prepared by many methods such as:
• Film-deposition on carrier method.
• Spray drying method.
J Nanomed Nanotechnol, an open access journal
ISSN: 2157-7439
Spray drying method
The distinctive attribute of this process is reclined in its propensity
*Corresponding author: Saiqua Muneer, University of Queensland, Australia, Tel:
61469085227; E-mail: [email protected]
Received: June 07, 2017; Accepted: June 24, 2017; Published: June 29, 2017
Citation: Muneer S, Masood Z, Butt S, Anjum S, Zainab H, et al. (2017)
Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review. J
Nanomed Nanotechnol 8: 448. doi: 10.4172/2157-7439.1000448
Copyright: © 2017 Muneer S, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Volume 8 • Issue 3 • 1000448
Citation: Muneer S, Masood Z, Butt S, Anjum S, Zainab H, et al. (2017) Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review. J
Nanomed Nanotechnol 8: 448. doi: 10.4172/2157-7439.1000448
Page 2 of 5
Water
outlet
Vacuum
pump
Water inlet
Motor
Flask
Solvent
Water bath
Heater
Figure 1: Apparatus for preparing PLs by film deposition on Carrier method.
Stage 1
Atomization
Stage 2
Spray-air contact
Stage 3
Droplet drying
Stage 4
Product collection
Figure 2: Apparatus for preparing PLs by Spray drying method.
to include particle composition and drying together in a consistent
stride, permitting more desirable production of particles. This method
can be used for any of the aqueous or non-aqueous systems for particles
production. Predominantly, this process is utilized when invariable
sized and shaped particles are needed and can be simply scaled up. Its
price is effectual and acceptable for massive preparation of PLs [14,15].
As shown in Figure 2, this spray drying procedure consists of
four phases: atomization of the product into a spray nozzle, spray-air
association, drying of the spray droplets and collection of the solid
product [16]. Firstly, preparation of liquid dispersions carrying pure
lipid or lipids and carriers in organic mixture is done and then it is
poured into the dry cell. By utilizing a spray nozzle, dispersions are
atomized into drying cell and desiccated in a simultaneous air flow
which is then gathered in a tank [16]. Prime factors which affecting
this method are high temperatures, shearing stresses and absorption
episodes and these can result into the thermal and mechanical
degradation of active molecules. It can be upgraded by making the
working variables better. Examples of working variables are drying air
temperatures and liquid spraying rate. For shielding the unification
of active molecules, stabilizing adjuvants e.g. disaccharides, cyclic
oligosaccharides and polyols can be utilized and by augmenting the
J Nanomed Nanotechnol, an open access journal
ISSN: 2157-7439
surface area of lipids, the effectiveness of hydration can be intensifying
[14,15].
Supercritical anti-solvent method
In Super critical anti-solvent method for the production of PLs we
use Supercritical Carbon dioxide (SCCO2) which actually is carbon
dioxide’s fluid state when it is held at on some level above its critical
temp and pressure.
Because of three main factors which includes
• Lower residual solvents,
• Simple steps,
• Mild operation temperatures.
We use anti-solvent technology for the preparation of PLs. An
apparatus consisting of three parts (e.g. a sample delivery unit, a
precipitation unit and a separation unit) is basically used in those
simple steps. Two pumps, one for the delivery of CO2 which is supplied
through CO2 cylinder (72 cm3) after being cooled down by refrigerator
and a high pressure pump is used introduce it to the buffer tank (-7°C)
for preheating thus The conditions of temperature and pressure of the
Volume 8 • Issue 3 • 1000448
Citation: Muneer S, Masood Z, Butt S, Anjum S, Zainab H, et al. (2017) Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review. J
Nanomed Nanotechnol 8: 448. doi: 10.4172/2157-7439.1000448
Page 3 of 5
reaction vessel or CO2 cylinder should be 45°C and 10 MPa and one for
the drug solutions which is introduced via HPLC pump combines up
to make the sample delivery unit [17]. Solvent which are completely
miscible with CO2 should be used for dissolving the drugs. For both
preparations, phospholipids, cholesterol, and drug were dissolved in
organic solvents followed by sonication until a clear and homogeneous
solution was obtained. For the entrance of CO2 into the vessel through
nozzle valves A and B will be opened. CO2 is sprayed through the
outer tubule whereas the solution is sprayed though inner tubule of
the nozzle. The second part of the apparatus consists of heated by air
bath vessel, and the last part comprises wet gas meter and a separator.
SCCO2 is separated from organic solvent in the last part’s separator
because of its low pressure and on the other hand wet gas meter is used
to measure the CO2 [18]. After reaching the preset value of temp and
pressure, valve A is open for the entrance of CO2 right after that, valve B
allow drug solution to enter the nozzle. Solution is mixed with SCCO2
and diffused into each other rapidly like it is sprayed through coxial
nozzle. Thus the solute will dissolve in organic solvent to reach supersaturation in a very short period of time about 30 minutes and this
all because of the solubility of solute in the organic solvent decreases
gently, thus the PLs are precipitated in the vessel. After the complete
utilization of solution, A and B valves are closed and valve C is opened
to depressurize the vessel at the opening temp and in the end we collect
these samples at the bottom of vessel on the filter. The pressure, temp
and the flow rate of the drug solution need to be optimized to obtain
the high drug loading PLs.
Fluidized bed method
On the large scale production of PLs whose principle relays on
particle coating technology, in which carrier material can vary from
crystalline powder to non pareil beads. While using non pareil beads as
carrier material, first for getting smooth surface pareil beads are coated
with seal coating which can help further in coating of phospholipids
and which also ensure thin uniform coating formation of phospholipids
around the core and small sized liposomes upon hydration. Carrier
material are then sprayed with the solution of organic solvent and
solution of drugs through nozzle, and by applying vacuum at the same
time to the fluid bed organic solvent is removed. The trace amount of
residual solvent is removed by the finished lipid-coated powder/beads
when dried under vacuum overnight (Figure 3).
Advantages include;
• Well establish and processable Film coating technology
• Number of various ways of coating
• Cost effective method [19,20].
Evaluation of Proliposome
Scanning electron microscopy (SEM)
It is used to observe surface structure of the PL powder. It includes
the comparison of the image of liposome and pure carrier material.
Carrier material in the formulation confirms the disposition of
phospholipids on the carrier and thus proliposomes formulation
confirms [21].
Transmission electron microscopy (TEM)
This method is also used to check the structure of liposomes
after PL powder hydration. In this process hydrate the proliposome’s
powder with distilled water and then view lamellarity and the shapes
under microscope [8,10,21].
Hydration study
Hydration study is carried out on the fact that liposomes are
formed on contact with aqueous environment. In this method we place
small quantity of dry powder of pro-liposomes and place it on a glass
slide and then gradual addition of water in it and is observed by using
microscope to view vesicle formation. During hydration dissolution
and disintegration occur rapidly as soon as hydration. Liposomes are
formed when the water come in contact with the lipid surface of proliposomes. This process continuous tills the complete hydration lipid
layer and carrier dissolution [22].
Zeta potential
Surface charge of particle can be determined by the zeta potential. It
is the potential difference between electro neutral region of the solution
and surface of tightly bound layer (shear place) [23].
Flow property
Content uniformity and handling processing operation can
be explained by the flow property of a powder formulation. For a
formulation based on solid powder it is necessary to analyse the
pro-liposome’s property. It can be assessed by measuring following
parameters; Angle of repose, Carr’s Index and Hausner’s ratio [11,22].
Solution
SC-CO2
CO2 Solution
Solution
SC-CO2
SC-CO2
CO2
CO2
Figure 3: Fluidized bed method.
J Nanomed Nanotechnol, an open access journal
ISSN: 2157-7439
Volume 8 • Issue 3 • 1000448
Citation: Muneer S, Masood Z, Butt S, Anjum S, Zainab H, et al. (2017) Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review. J
Nanomed Nanotechnol 8: 448. doi: 10.4172/2157-7439.1000448
Page 4 of 5
Applications
Pro-liposomes can be formulated for the below mentioned routes
of administration.
Parenteral delivery
For parenteral application, most important is their sterilization.
Sterilization techniques commonly used are steam sterilization,
γ-irradiation, aseptic manufacturing and filtration sterilization.
Terminal sterilization is not appropriate for liposomal formulations as
it requires steam at 121°C. At high temperature liposome structure is
destroyed because of lipid hydrolysis and boosts the per oxidation of
unsaturated lipids [24,25]. Pro-liposomes are adequate for parenteral
delivery of liposomes. The benefit linked with Pro-liposomes is that it
permits sterilization without affecting the intrinsic characteristics [26].
Pro-liposomes can be stored in dry form after sterilization and can
be hydrated before administration to form multi-lamellar liposomal
suspension [27]. In the past few decades, Pro-liposomes played a
vital role in the area of injectable drug delivery system. Entrapment
of drug into multi-vesicular liposomes leads to novel approach in
sustained release drug delivery. Liposomal entrapment of drug results
in sustained release lasting over several days to weeks [28].
Oral delivery
Pro-liposomes help to enhance the dissolution efficiency of
poorly soluble drugs. It produces multi-lamellar vesicles on contact
with fluid which guarantees higher entrapment of insoluble drugs
due to widened hydrophobic volume within the liposomal lamellae.
It also permits conversion of drug from crystalline to amorphous
form [2]. Improvement in bioavailability of drugs having extensive
first pass metabolism and increased lymphatic uptake is due to larger
particle size of multi-lamellar liposomes formed on hydration [29].
Pro-liposomes are formulated to increase stability of liposomes.
Formulations improve solubility and bioavailability of some poorly
soluble drugs. Domperidone is a specific 5HT3 receptor antagonist
used as anti-emetic. Domperidone is poorly soluble in water and
after oral administration it undergoes extensive gastric and hepatic
first pass metabolism. This leads to very low oral bioavailability that
will not produce its required therapeutic effect. Pro-liposomes of
Domperidone are formulated in order to increase bioavailability by
enhancing intestinal permeability that results in improved lymphatic
uptake and circumventing first pass metabolism [30]. Pro-liposomal
formulations are now extensively used for drugs having low aqueous
solubility like Exemestane [31], Salamon Calcitonin [32], Glyburide
[33], Halofantrine [34] and Progesterone [35].
Pulmonary delivery
Liposomal preparations are also formulated for localized drug action
in the respiratory tract. As liposomes are composed of phospholipids
that are also a part of lung surfactant thus, drug entrapment within
the liposomes result in improved absorption. Drugs encapsulated in
Liposome are present in blood for extended period of time and with
decreased adverse effects [36,37]. Pulmonary drug delivery is attained
by following three types of devices:
Pressurized metered dose inhalers (pMDI): Drugs solution or
suspension are added to liquefied propellants. Hydrofluroalkanes are
used instead of Chlorofluorocarbons as they are non-ozone depleting
propellants but they are poorly soluble in phospholipids. Pro-liposomes
can be suspended in these propellants and act as as carrier of liposomes
for pulmonary route [36].
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ISSN: 2157-7439
Dry powder inhalers (DPIs): It involves the inhalation of drug as
fine powder that causes dispersion of drug directly into airstream of
patient. Dry powder inhalers have numerous benefits like controlled
delivery, decreased toxicity and enhanced potency, even displacement
of drugs locally, increased patient compliance, improved stability and
large amount of drug entrapment. Pro-liposome formulations are in
dry powder form so they are used preferably for liposomes delivery
by dry powder inhaler [36]. Spray dried liposomes entrapped Dapsone
dry powder inhaler have extended drug action in lungs to impede
Pneumocystis carinii pneumonia. In vitro studies predict 16 hours
prolonged drug release [38].
Nebulizers: It is the simplest method for providing liposomes to
the respiratory system but it can be upset by liposome leakage and
drug instability. Dry powder formulations are used to get rid of this
problem. So, pro-liposomes are strong carriers of liposomes through
nebulization [36,37].
Mucosal delivery: Pro-liposomes on contact with aqueous mucosal
surfaces transformed into liposomes. Phospholipids are the component
of pro-liposomes which are non-toxic, non-irritant and compatible
with biological membranes. The molecular dispersion of drug into
bilayer results in increased therapeutic action [39]. The vaginal proliposomal formulation of Clotrimazole has prolonged release of drug
and may improve the drug retention time within the mucosa that leads
to better antifungal effect [40].
Transdermal delivery: Pro-liposomes are composed of
phospholipids that have natural affinity for skin lipids and thus enhance
the drug permeation within the skin. Pro-liposomes on hydration are
converted to liposomes that lead to sustained action of entrapped drug.
Liposomes developed on contact with aqueous environment regulate
diffusion across the skin. Hence the permeation of skin is increased
by avoiding the stratum corneum hindrance [40,41]. Aceclofenac
and Nicotine proliposomal formulations have been formulated for
sustained transdermal action [41].
Ocular drug delivery: Conventional ocular drugs have poor
bioavailability because of precorneal loss effects. Pro-liposomes are
used to enhance the drugs bioavailability and their therapeutic action.
Drugs entrapped within the lipid bilayer of liposomes have high
solubility and can traverse cornea. Liposomal formulations can easily
be used for ocular drug delivery. Liposomal hydrogels of Ciprofloxacin
are used in order to prevent catheters from bacteria [41].
Conclusion
Pro-liposomes have provided a major breakthrough in solving the
stability issues associated with liposomes. It has also opened newer areas
of liposome application. Significant progress has been made towards
the development of pro-liposomes as useful oral dosage forms although
there are no marketable products. Reviews on oral pro-liposomes
have highlighted several issues of importance that include complexity
of experimental design, variability in response ,multiplicity of
formulation variables and stability problems in GI tract. Pro-liposome
have been used on a broad range of pharmaceutical application. The
pro-liposomes are administrated orally, parenterally and topically
as well as used in cosmetic and hair technologies, sustained release
formulations, diagnostic purpose and as good carriers in gene delivery.
Nowadays pro-liposomes are used as versatile carriers for targeted
delivery of drug. However based on these we can say that Pro-liposome
have definitely established their position in modern delivery system.
Volume 8 • Issue 3 • 1000448
Citation: Muneer S, Masood Z, Butt S, Anjum S, Zainab H, et al. (2017) Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review. J
Nanomed Nanotechnol 8: 448. doi: 10.4172/2157-7439.1000448
Page 5 of 5
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Citation: Muneer S, Masood Z, Butt S, Anjum S, Zainab H, et al. (2017)
Proliposomes as Pharmaceutical Drug Delivery System: A Brief Review. J
Nanomed Nanotechnol 8: 448. doi: 10.4172/2157-7439.1000448
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